This Program Grant focuses on the hypothesis that chronic rhinosinusitis, a disease affects approximately 15% of Americans, is due to epithelial cell dysfunction. This dysfunction may arise from an inherent genetic defect(s), environmental influences, or most likely, a combination of the two. This project contributes to this hypothesis by testing whether viral infection is an important environmental stimulus in the development and exacerbation of chronic rhinosinusitis by triggering alterations in epithelial cell function, particularly increased production of pro- inflammatory cytokines, including IL-8, GM-CSF, RANTES and eotaxin. To examine the relationship between viral infection and chronic rhinosinusitis we will monitor subjects prospectively following endoscopic sinus surgery to determine if nasal and sinus secretions from subjects experiencing exacerbations of rhinosinusitis show a higher incidence of viral infection, detected by PCR, compared to secretions obtained from the same subjects during periods when disease activity is less severe. Given that nitric oxide (NO), is antiviral and inhibits epithelial cytokine production, we also will test the hypothesis that an inability of the sinus epithelium to increase production of NO, via the enzyme inducible NO synthase (iNOS), during viral infections is a risk factor for chronic rhinosinusitis. We will examine the mechanism of induction of iNOS by rhinovirus in cultured epithelial cells and will determine if subjects with chronic rhinosinusitis show lower induction of epithelial iNOS expression, and increased epithelial cytokine production and inflammation, compared to normal subjects during experimental rhinovirus infections. Intranasal glucocorticoids are currently advocated as an appropriate therapy to reduce disease recurrence in patients after sinus surgery. Despite widespread use for this identification, however, the efficacy, and mechanisms glucocorticoids versus placebo in subjects recruited after sinus injury to test the hypothesis, which is based upon in vitro data, that topical glucocorticoids will reduce epithelial expression of GM-CSF, RANTES, and eotaxin, and tissue eosinophilia in subjects but will have little effect on epithelial expression of IL-8 or on neutrophilic inflammation. We suggest that such an outcome will result in only a partial therapeutic effect. These studies should provide important insights into the pathogenesis of chronic rhinosinusitis and may lead to the development of improved therapies for the treatment of this major health problem.